Hyperhomocysteinemia is graded risk factor for atherosclerotic cardiovascular diseases, a leading cause of mortality in the United States. Two housekeeping enzymes that directly "manage" cellular homocysteine are methionine synthase (MS) and cystathionine Beta-synthase (CBS). The human genes encoding both proteins have been cloned, and mutations in these genes leading to severe hyperhomocysteinemia have been described. Polymorphisms in these genes independently, or in concert with the environment (viz. Nutritional status), may contribute to mild hyperhomocysteinemia. The proposed goals are (1) to test the hypothesis that one or more common polymorphisms in the MS gene correlates with "risk" for cardiovascular diseases. (2) To develop rapid genetic and biochemical screens for detecting MS mutations in patients (3) To characterize the cellular and organismal consequences of severe MS deficiency using a cell culture model and MS knockout mice. (4) To characterize the catalytic penalties attendant with individual mutations in CBS isolated from homocystinuric patients and MS polymorphisms that have been discovered so far. (End of Abstract)